On December 31, 2009, Byrd signed a three year, $15 million contract with the Chicago Cubs.[6] In his first season with the Cubs, Byrd had his best season. He was selected for his first All-Star Game, Byrd entered the game as a substitute and drew a walk off of Matt Thornton. He scored from first base on a double by the Braves' Brian McCann. In the ninth inning, while playing right field, Byrd made an outstanding play, forcing David Ortiz at second after fielding what normally would have been a base hit. Also, a popular saying among Cubs fans is "The Byrd is the Word."

On May 21, 2011, while batting during the 2nd inning of a game against the Boston Red Sox at Fenway Park, Byrd was hit near his left eye by a pitch from Red Sox pitcher Alfredo Aceves. The pitch was, according to Aceves, unintentional. After the pitch hit him, Byrd dropped to the ground, covered the area by his left eye and rolled in pain; he was helped off the field by Cubs medical personnel and taken to the trainer's room in the clubhouse. Byrd did not return to the game. He was taken to Massachusetts Eye and Ear Infirmary atMassachusetts General Hospital in Boston, where he stayed overnight to be examined. The incident marked the fifth time that Byrd had been hit by a pitch in a ten-day period.[7] Byrd was placed on the 15-day disabled list the following day. Justin Berg was called up to take his place.[8] Since coming off his stint on the disabled list, Byrd has worn a protective mask customized to his helmet in order to shield his weakened facial bones.

After the 2011 season Byrd began practicing Muay Thai and started a new diet, he has lost 40 pounds and expected to have his best season in 2012.[9]